Three-year outcome following neonatal encephalopathy in a high-survival cohort

This study investigated the 3-year clinical outcomes in relation to the severity of encephalopathy in high-survival infants who underwent therapeutic hypothermia. This retrospective observational study was conducted in level II/III neonatal intensive care units in Japan. The nationwide cohort included 474 infants registered in the Baby Cooling Registry of Japan between January 2012 and December 2016. Clinical characteristics, mortality rate and severe neurological impairment at age 3 years were evaluated. Of the infants, 48 (10.4%), 291 (63.1%) and 122 (26.5%) had mild, moderate and severe encephalopathy, respectively, upon admission. By age 3, 53 (11.2%) infants died, whereas 110 (26.1%) developed major disabilities. The mild group survived up to age 3. In the moderate group, 13 (4.5%) died and 44 (15.8%) developed major disabilities. In the severe group, 39 (32.0%) died by age 3. Adverse outcomes were observed in 100 (82.0%) infants. Mortality was relatively low in all subgroups, but the incidence of major disabilities was relatively high in the severe group. The relatively low mortality and high morbidity may be due to Japanese social and ethical norms, which rarely encourage the withdrawal of intensive life support. Cultural and ethical backgrounds may need to be considered when assessing the effect of therapeutic interventions.

By contrast, mild HIE has rarely been a focus of study, as its prognosis is generally considered favourable 5,[12][13][14] . However, a recent study of 43 infants found that 16% of uncooled infants with mild HIE had neurological impairments by age 18-22 months 15 . Despite the lack of clinical evidence to support the benefit of therapeutic hypothermia for infants with mild HIE, a considerable proportion of these infants have received such treatment in Western countries 16,17 . However, such a 'therapeutic creep' has not been as apparent in Japan, possibly due to a nationwide dissemination campaign encouraging physicians to adhere to evidence-based therapeutic hypothermia regimens 18 .
Thus, for an appraisal of preferred neuroprotective regimens, domestic backgrounds, such as cultural and ethical backgrounds and local adherence to evidence-based guidelines, may need to be considered. To facilitate comparisons of the benefits of cooling among studies conducted in different countries, clinical outcomes need to be assessed in conjunction with the level of HIE severity.
Thus, this study aimed to review the 3-year mortality rate and incidence of severe neurodevelopmental impairments according to the initial HIE severity in a Japanese cohort of infants with a high survival rate following therapeutic hypothermia.

Results
Final study cohort. Clinical data were obtained from 756 infants, who were registered at 110 intensive care units over the 5-year window period. Among these infants, 474 (62.7%, final cohort) had outcome data at 3 years of age; 282 were lost to follow-up (Fig. 1). The baseline characteristics were similar between those with and without follow-up data; an exception to this was that the encephalopathy stage was more severe among infants in the final study cohort (Table 1).  Encephalopathy stages and outcomes. All 48 infants diagnosed with mild encephalopathy upon admission survived to 3 years of age without hearing loss, blindness or requirement for chronic healthcare. Of the infants with mild encephalopathy, 4.2% (2/48) had a major disability; one infant was diagnosed with cerebral palsy (GMFCS level 3), while another infant was diagnosed with both cerebral palsy (GMFCS level 5) and epilepsy (Table 2). Of the 291 infants diagnosed with moderate encephalopathy upon admission, 13 (4.5%) died, while 44 (15.8%) survivors developed a major disability; 57 (19.6%) cases of composite adverse outcomes were recorded. Among survivors, 21 (7.6%) were dependent on respiratory support or tube feeding. At 3 years of age, 10 (3.6%), 5 (1.8%), 5 (1.8%), 30 (10.8%) and 35 (12.6%) children exhibited hearing loss, blindness, epilepsy, GMFCS > 2 and MACS > 2, respectively ( Table 2).

Discussion
In a cohort of infants with high-survival rate from the Japanese national registry, the relationship between the severity of encephalopathy and outcomes following therapeutic hypothermia differed from that reported in other developed countries 5,21 . The 3-year outcomes of Japanese HIE infants were characterised by consistently www.nature.com/scientificreports/ low mortality rates for those diagnosed with mild, moderate and severe encephalopathy (0.0%, 4.5% and 32.0%, respectively), as well as a relatively high rate of major disabilities in survivors of severe encephalopathy (73.5%). The social and ethical norms in Japan, which do not allow the withdrawal of intensive life support (despite severe neurological impairment) may have accounted for the low mortality and high morbidity rates observed among infants with severe encephalopathy.
A meta-analysis based on clinical studies from Western countries reported mortality rates of 13.5% and 52.4% in infants with moderate and severe neonatal encephalopathy, respectively, following therapeutic hypothermia 5 ; these rates were considerably higher than the mortality rates documented among Japanese infants in the present study (4.5% and 32.0%, respectively). Another study utilising an international registry in The Children's Hospitals Neonatal Database (n = 945) reported hospital mortality rates of 3.5% and 46.8% for infants with moderate and severe encephalopathy, respectively. The majority of deaths (82.4% and 86.1% of deaths following moderate and severe encephalopathy, respectively) occurred after the withdrawal of life-sustaining support 21 . Although our current study did not collect information regarding withdrawal of intensive life support, our prior study showed that even among infants with most severe encephalopathy (with 10-min Apgar scores of zero), only 2 of the 9 (22.2%) died following withdrawal 11 . In the current study, the rate of major disability among survivors of severe encephalopathy was 73.5%, which was relatively higher than the morbidity rate (36.8%) reported in a previous study 5 . The association of severe encephalopathy with the combination of low mortality (32%) and high morbidity (57%, severe disabilities) was also observed in a previous study conducted among severely asphyxiated infants (10-min Apgar scores of zero) in Japan 11 . These findings may be attributed to the reluctance among physicians in Japan to withdraw intensive life support, even in the most severe cases of encephalopathy. Future studies of neuroprotective treatments may need to consider the influence of local social and ethical backgrounds to more accurately assess the effect of therapeutic hypothermia on long-term morbidity and mortality rates.
To date, only a few studies have addressed the outcomes of infants with mild HIE at or beyond 18 months of age 22,23 . However, recent studies have reported that these infants are at a risk of adverse outcomes, such as behavioural problems and neurodevelopmental impairments 24,25 . For example, a multicentre cohort study demonstrated that 16% of infants with mild encephalopathy who did not undergo therapeutic hypothermia had cognitive developmental quotients of < 85, while approximately 40% had at least one cognitive, motor or language score of < 85 15 . In the present study, only 4.2% of infants with mild encephalopathy developed adverse outcomes at 3 years of age. In this study, the majority of the registered infants had moderate to severe HIE; this is perhaps due to the Baby Cooling Registry of Japan specifically recruiting infants who underwent therapeutic hypothermia and the strict adherence to international guidelines in Japan, where therapeutic hypothermia is considered only in cases with moderate to severe HIE 18 . It is possible that the HIE severity in the 48 patients with mild HIE in this study was different from that in previous studies. Although both the mortality rate and long-term outcome of these infants were optimal, the influence of therapeutic hypothermia remains unclear. Further studies are required to determine whether therapeutic hypothermia is beneficial in this cohort of infants.
We were able to elucidate the relationship between the severity of encephalopathy, as assessed in infants upon admission, and long-term outcomes. This was achieved by assessing a high-survival cohort from a large registry in Japan. However, several limitations should be considered. First, 37.3% of the infants were lost to follow-up. The follow-up rate was lower in infants with mild encephalopathy, presumably reflecting the optimistic perspective of the neurological outcome and subsequent cessation of follow-up. Therefore, our current findings may predominantly reflect outcomes associated with infants with relatively more severe disease. Second, as the assessment of neurological outcomes using individualised batteries was only performed in 40% of the study population, the use of standard outcome measures was problematic. Similarly, we were unable to incorporate potential independent variables of outcomes within the analysis, such as the type of respiratory care, use of inotropic support, incidence of pulmonary hypertension and seizures and findings of amplitude-integrated electroencephalogram (aEEG) and MRI, because the type, dose and duration of supportive treatment and assessment of ultrasound sonography, aEEG and MRI significantly differ between participating units 26 . The evaluation of outcomes focused on chronic healthcare needs and motor function, but not on cognitive or language function, as reported in previous studies [27][28][29] . Third, although the Baby Cooling Registry of Japan disseminated tools and domestic guidelines for the evidence-based implementation of therapeutic hypothermia, including the precise assessment of encephalopathy using the Sarnat encephalopathy staging 12 and the Thompson encephalopathy scoring 30 , the classification of the severity of encephalopathy was not standardised for this particular registry across centres. Recently, Chalak et al. demonstrated that the long-term outcomes of encephalopathic infants can be predicted using a relatively more objective categorisation of the modified Sarnat scoring criteria 31 . This may improve patient selection in future prospective studies.
In conclusion, the incidence of death and major disability following mild, moderate and severe HIE was reviewed for a large-scale national cohort in Japan. Mortality was relatively low in all subgroups (patients were stratified based on HIE severity), whereas the incidence of major disabilities was relatively high in infants with severe HIE. Cultural and ethical backgrounds, as well as the quality of medical care, may need to be considered when assessing the benefits of therapeutic interventions for HIE. Although the outcomes of infants with mild HIE appeared to be optimal following therapeutic hypothermia, the benefit of such treatment for this cohort of infants needs to be validated further. The natural outcomes associated with mild HIE and the neuroprotective effect of therapeutic interventions need to be addressed in future studies.

Methods
Population and data collection. The Baby Cooling Registry of Japan is an online case registry that was established in January 2012 and includes patient data from all registered Japanese level II/III neonatal intensive care centres. The details of this registry have been reported previously 18 . This observational study was based on 3-year outcome data from 474 infants registered between January 1, 2012, and December 31, 2016 (Fig. 1).

Assessment of outcomes.
The outcomes of cooled infants were assessed at 3 years of age according to the protocol of the Baby Cooling Registry of Japan 18 . The infants' parents were asked to assess the outcome of their cooled infants at 18 months postconceptional age and 36 months chronological age by consulting a neonatologist, paediatrician or child neurologist. Data pertaining to the following variables were collected: hearing loss; blindness; epilepsy (requiring anticonvulsant treatment); chronic healthcare needs (e.g., requirements for tube feeding, gastrostomy, tracheotomy or prolonged ventilator management upon reaching the age of 3 years old); and neuromotor function assessed using the GMFCS 19 and MACS 20 . GMFCS and MACS scores range from 0 to 5, with higher scores indicating greater impairment. Major disability was defined as survival with at least one of the following conditions: requirement for tube feeding or respiratory support, hearing loss, blindness, epilepsy, GMFCS > 2 or MACS > 2.
Statistical analysis. The primary outcome was death or major disability upon the 3rd year of follow-up.
To assess potential bias due to follow-up loss, baseline characteristics were compared between children with and without follow-up data at 3 years of age

Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.